Survivin is a 16.5 kDa intracellular protein that belongs to the inhibitor of apoptosis protein (IAP) family. Survivin acts in concert with the mitotic spindle apparatus to regulate cell division. It is expressed in certain cells during the G2/M phase of the cell cycle and associates with the spindle microtubule organizing center during this phase of cell cycle progression [Zhao J, et al. (2000) J Cell Sci, 113:4363-71; Li F, et al. (1998) Nature, 396:580-4; Fortugno P, et al. (2002) J Cell Sci, 115:575-85]. Survivin has also been shown to modulate the function of certain caspases, directly inhibiting apoptosis [Tamm I, et al. (1998) Cancer Res, 58:5215-20; Conway et al. (2000) Blood 95:1435-42; Shin S, et al. (2001) Biochemistry, 40:1117-23]. In addition, survivin inhibits the cyclin D/cdk4 complex [Fukuda S, Pelus L M. (2002) Cell Cycle, 1(5):322-6], permitting cell cycle progression. Thus, survivin functions in critical roles at a number of different cellular loci to regulate the cell cycle and to inhibit apoptotic cell death.
Survivin is overexpressed during the G(2)/M phase of the cell cycle in most cancer cells and is one of the most specific cancer antigens identified to date. It is expressed in a large percentage of tumors and is rarely detectable in normal adult tissues [Overwijk W W, et al. (1998) J Exp Med, 188:277-86; Adida C, et al. (1998) Am J Pathol 152:43-49]. Although survivin is expressed in some instances within CD34(+) hematopoietic stem and progenitor cells that have been stimulated by hematopoetic growth factors, it is generally not presented on the surface of these cells. [Fukuda S, Pelus L M. (2002) Cell Cycle. 1(5):322-6].
It has recently come to light that survivin-expressing cells that mediate autoimmune processing (SECMAPs), such as synovial cells, are involved in certain autoimmune disorders express survivin in their pathogenic state. Examples of such cells include but are not necessarily limited to macrophages, T cells and fibroblasts. Autoimmune disorders that have been positively correlated with the presence of SECMAPs include but are not necessarily limited to arthritis, and particularly rheumatoid arthritis, and multiple sclerosis (see, for example, for arthritis: Smith, et al. Rheumatology (Oxford). 2010 Feb. 10. [Epub ahead of print]; Svensson et al. Ann Med. 2010; 42(1):45-54; Baran et al., J Cell Mol Med. 2009 Feb. 27. [Epub ahead of print]; Dharmapatni et al., Arthritis Res Ther. 2009; 11(1):R13; et al. Clin Exp Rheumatol. 2008 September-October; 26(5):881-6; Galeotti et al., Clin Exp Rheumatol. 2008 March-April; 26(2):373-8; Gagarina et al. J Biol Chem. 2008 Jan. 4; 283(1):648-59; Bokarewa et al. Scand J. Immunol. 2007 August-September; 66(2-3):192-8; Markham et al. Br J. Dermatol. 2006 December; 155(6):1191-6; Hanashi et al. Clin Exp Rheumatol. 2005 July-August; 23(4):550; Bokarewa et al. Arthritis Res Ther. 2005; 7(2):R349-58; and for multiple sclerosis: Hebb et al. Mult Scler. 2008 June; 14(5):577-94; Sharief et al. Eur J. Neurol. 2002 September; 9(5):503-10; Sharief et al. Arch Neurol. 2002 July; 59(7):1115-21; Sharief et al. J. Neuroimmunol. 2001 Oct. 1; 119(2):358-64).
Thus, there is an ongoing and unmet need for compositions and methods for prophylaxis and/or therapy of autoimmune disorders that are caused and/or sustained at least in part by the activity of SECMAPs.